Nat Genet:从基因层面找到“渐冻症”发病机理

2019-07-26 Paris 转化医学网

还记得风靡全球的“冰桶挑战”吗?它将“渐冻症”带进了公众的视野,让越来越多的人了解到这一罕见病,同时也让我们更多得了解到神经退行性疾病,譬如阿尔茨海默病,但同时,我们也越来越深刻地认识到了人类对神经退行性疾病的束手无策,据专家分析,在不久的将来,神经退行性疾病极有可能超越癌症成为人类一大致死率极高的疾病。

还记得风靡全球的“冰桶挑战”吗?它将“渐冻症”带进了公众的视野,让越来越多的人了解到这一罕见病,同时也让我们更多得了解到神经退行性疾病,譬如阿尔茨海默病,但同时,我们也越来越深刻地认识到了人类对神经退行性疾病的束手无策,据专家分析,在不久的将来,神经退行性疾病极有可能超越癌症成为人类一大致死率极高的疾病。

近日,科学家们终于拨开云雾,来自东京大学医学院的研究团队从基因层面找到了神经退行性疾病发病机理,为该类疾病的进一步研究奠定了理论基础,也为其治疗开辟了新的格局。相关文章以“Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease”为题同步发表在核心期刊《Nature genetics》上。

以脆性X震颤/共济失综合征为例,研究人员对其发病机制进行了进一步的解读,脆性X相关震颤/共济失调综合征(fragileX-associated tremor/ataxia syndrome,FXTAS)是一种晚发型神经系统退行性疾病,由X染色体智能低下1型(fragile Xmental retardation 1,FMR1)基因的前突变(premutation)引起,临床主要表现为意向性震颤、小脑性共济失调、帕金森症候群、认知功能减退、周围神经病及自主神经功能障碍。

而其遗传原因早在21世纪初就已被归咎于遗传密码CGG的非编码重复扩张。具体来说,这一行为可引起各种神经肌肉疾病,包括肌强直性营养不良,脆性X震颤/共济失调综合征,一些脊髓小脑性共济失调,肌萎缩侧索硬化和良性成人家族性肌阵挛性癫痫。通过对各类神经退行性疾病的研究发现, FMR1中非编码CGG重复扩增引起的神经元核内包涵体疾病(NIID)和脆性X震颤/共济失调综合征的临床症状及神经影像学具有的惊人相似性,是以,受此启发,他们直接在NBPF19中搜索重复扩增突变并鉴定非编码CGG的重复扩增行为。


通过分析全基因组序列数据的短片短直接鉴定重复扩增突变

想要在人类的46条染色体中搜索CGG序列如同大海捞针,Shinichi Morishita教授将基因组测序与数据分析相结合,开发了一种新的计算机程序,对所有这些短序列进行排序,搜索由CGG组成的序列。 使用整个健康人类基因组的标准序列,计算机程序可以将包含CGG重复突变的那些DNA片段固定到特定的遗传领域。在这一领域,研究人员可将他们的搜索范围缩小到基因组中的任何地方,以明确鉴定基因,以及基因在患者CGG重复突变中的位置。

功夫不负有心人,通过搜索他们发现,在基因组的不同区域发现了相同的基因突变,且该突变导致了不同的疾病。这简直颠覆了我们之前的认知:不同的基因突变可导致相同的疾病,譬如说,帕金森氏病可由至少五种基因的独特突变引起,而囊性纤维化甚至可由同一基因中的1,000多种不同突变引起。

鉴定NIID中NBPF19中的CGG重复扩增突变

这一新发现为更多了解其他神经退行性疾病奠定了理论基础,另外,近日科学家还发现了肠道微生物及代谢物对小鼠“渐冻症”的潜在影响。我们相信越来越多机理和标志物的发现,一定会改变“渐冻症”的治疗现状。

原始出处:Hiroyuki Ishiura, Shota Shibata, Jun Yoshimura, et al. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat Genet. 22 July 2019

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    2020-05-29 canlab
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    2020-06-01 liye789132251
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    2020-06-14 cy0324
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    2019-07-28 xjy02
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    2019-07-27 坚强007

    向科研人员致敬!向科研人员致敬!

    0

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Nature Genetics:这个基因竟与四种罕见神经退行性疾病都有关

神经退行性疾病一直是医学研究难以攻克的一大疾病,像是阿尔茨海默症、帕金森、癫痫、亨廷顿病等都是我们所熟悉的神经退行性疾病。当然,对于一些罕见的神经退行性疾病科学家也没有放弃。同一种疾病可能是由于不同的基因突变导致的,这就使得许多遗传性疾病治疗变得复杂。如果能够找到其中的共同点,或将为治疗带来新方法。

Sci Rep:转移前列腺癌中HOXB13同源异型盒基因能够调控有丝分裂蛋白激酶互作网络

HOXB13是一个同源异型盒转录因子,并且与根治性前列腺切除术后复发有关。虽然HOXB13能够以环境依赖的方式来调控雄激素受体(AR)功能,它在前列腺癌(PC)转移中的关键影响仍旧大部分未知。最近,有研究人员为了鉴定转移性PCs中HOXB13的转录靶标,在人类前列腺肿瘤特异性AR结合位点附近进行了综合的差异化基因表达(DEGs)生物信息学分析。无监督主成分分析(PCA)表明HOXB13靶基因聚焦于

科学家利用机器学习让耐药检测更高效

中国科学院微生物研究所冯婕研究组等针对肺炎链球菌β-内酰胺耐药这一重要临床问题,采用机器学习的方法挖掘耐药相关数据的规律,建立了基因型和表型之间的联系。

Cell Death Dis:IFITM3能够促进前列腺癌细胞的骨转移

晚期阶段前列腺癌(PCa)总是能够诊断出骨转移,并且治疗方法有限。转化生长因子β(TGF-β)能够诱导上皮-间质转化(EMT),并且TGF-β在骨基质中的丰度是重要的生长因素之一,并且有利于骨转移。据报道,TGF-β是骨转移的关键调控因子,但是潜在的机制仍旧不清楚。最近,有研究人员发现干扰素诱导的跨膜蛋白3(IFITM3)通过与Smad4结合激活TGF-β-Smads信号途径,在恶性肿瘤细胞增殖、